title: Interferon gamma causes olfactory dysfunction without concomitant neuroepithelial damage.
abstract: BACKGROUND
  Olfactory loss is a debilitating symptom of chronic rhinosinusitis (CRS). The pathophysiology of inflammatory olfactory dysfunction likely involves both conductive and sensorineural components. To study the interaction of CRS-associated inflammatory cytokines with the olfactory epithelium (OE), a transgenic mouse model was developed that allows temporally-controlled local gene expression. Interferon-gamma (IFN-γ) is a prototypical T helper 1 (Th1) cytokine linked to nonpolypoid CRS (CRSsNP), as well as sinonasal viral and bacterial infections. In this study, the effects of chronic IFN-γ expression on olfactory histology and function were investigated.
  
  
  METHODS
  IFN-γ secretion by olfactory sustentacular cells was induced in the transgenic mouse. Viability and gross behavior were unaffected. Mice were euthanized after 6 weeks of IFN-γ expression, and olfactory tissue was studied by histology, immunohistochemistry, and electro-olfactography (EOG). Findings were compared with uninduced littermates.
  
  
  RESULTS
  IFN-γ expression did not result in alteration of the normal histologic architecture of the neuroepithelium or lamina propria. However, EOG recordings demonstrated a significant decrease in odorant responses after IFN-γ expression. In addition, a marked increase in submucosal CD45-positive cells was observed, the majority of which were CD3-positive and CD4-positive lymphocytes.
  
  
  CONCLUSIONS
  Chronic IFN-γ expression in the mouse OE results in diminished odorant responsiveness, despite the absence of inflammatory tissue damage. This suggests a direct effect of IFN-γ on olfactory neuron function that may underlie olfactory loss in CRSsNP or viral infections. The infiltration of submucosal lymphocytes raises the possibility that other downstream cytokines also contribute to olfactory dysfunction.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Pozharskaya
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lane
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000473:pathology*; D017817:Nasal Lavage Fluid / Q000737:chemistry; D009831:Olfactory Mucosa / Q000473:pathology / Q000503:physiopathology
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens
keywords: interferon gamma; olfactory loss; rhinosinusitis; transgenic model